This invention relates to a multiple-unit sustained release tablet comprising a granular part and a powdery part.
Pharmaceutical preparations for controlling a dissolution rate of an active ingredient may be classified into a single-unit pharmaceutical preparation and a multiple-unit pharmaceutical preparation. The single-unit pharmaceutical preparation is mainly in the form of tablets, while the multiple-unit one is mainly in the form of capsules or granules. The multiple-unit pharmaceutical preparation is superior to the single-unit one in the following characteristics: (1) less change in absorption of an active ingredient, (2) easier reproducibility of dissolution, and (3) being applicable to two or more active ingredients. Due to these excellent features, the multiple-unit pharmaceutical preparation is desirable as a sustained release preparation. The multiple-unit pharmaceutical preparation is desirably in the form of tablets rather than capsules or granules so that it may be taken more easily.
However, the conventional multiple-unit sustained release tablet is prepared by coating core particles with a drug layer, coating the surface of said coated particles with a release-controlling agent to form sustained release granules, blending said granules with a powdery part and then compressing to tablets. A sustained release film of the granules may often be broken during compression to tablets, resulting in difficulty in controlling dissolution of the drug. For coping with these problems, there have been proposed multiple-unit tablets, which comprises a granule of an indefinite form and a powdery part, said granule being composed of an uncoated granule containing low-melting fats and oils and an active ingredient, and a release-controlling film (JP-A-7-316042), or sustained release compression tablets prepared by compressing numerous microcapsules composed of fine particles of an active ingredient, said active ingredient being coated with a sustained release polymer composition, wherein said microcapsules have non-uniform particle diameters within the range of from about 5 xcexc to about 400 xcexc and can be immediately disintegrated in an aqueous solution to disperse into individual microcapsules (Japanese Patent No. 2601660). However, sustained release granules according to the prior art having an indefinite and unequal shape would make it difficult to apply a uniform coating film and to prepare sustained release tablets with a stable dissolution rate.
The object of the invention is to provide multiple-unit sustained release tablets with little change in dissolution rate caused by compression during tableting step.
We have found that the above problems can be dissolved by using a granule comprising a matrix composed of a water-insoluble polymer and an active ingredient (hereinafter referred to as a matrix granule) or said matrix granule further coated with a release-controlling film (hereinafter referred to as a coated granule), upon which the present invention has been completed.
More specifically, the present invention includes the following inventions:
(1) A multiple-unit sustained release tablet characterized by consisting of a granular part and a powdery part, each granule in the granular part comprising a matrix composed of a water-insoluble polymer and an active ingredient.
(2) The multiple-unit sustained release tablet as described in the item (1), wherein said granule comprises a core particle and a matrix layer composed of a water-insoluble polymer and an active ingredient for coating said core particle.
(3) The multiple-unit sustained release tablet as described in the item (1) or (2), wherein a weight ratio of said water-insoluble polymer to said active ingredient is 0.7:1-3:1.
(4) The multiple-unit sustained release tablet as described in any of the items (1)-(3), wherein said water-insoluble polymer is ethyl cellulose.
(5) The multiple-unit sustained release tablet as described in the item (4), wherein said ethyl cellulose has a viscosity of not less than 15 cps at 25xc2x0 C. when dissolved at 5% by weight in a mixed solution of toluene and ethanol (8:2 w/w).
(6) The multiple-unit sustained release tablet as described in any of the items (1)-(5), wherein said granule is coated with a release-controlling film.
(7) The multiple-unit sustained release tablet as described in the item (6), wherein said release-controlling film is a water-insoluble polymer.
(8) The multiple-unit sustained release tablet as described in the item (6) or (7), wherein said water-insoluble polymer is ethyl cellulose.
(9) The multiple-unit sustained release tablet as described in any of the items (6)-(8), wherein said granule has a granule strength of not less than 3,000 g/mm2 in the state not coated with said release-controlling film.
The water-insoluble polymer as used herein means a water-insoluble polymer used in the pharmaceutical field as a sustained release coating agent, an enteric coating agent, a gastric coating agent, etc., which may include, for example, ethyl cellulose, purified shellac, white shellac, aminoalkyl methacrylate copolymer RS, hydroxypropyl methylcellulose phthalate, hydroxypropyl methylcellulose acetate succinate, carboxymethylethyl-cellulose, cellulose acetate phthalate, methacrylic acid copolymer L, methacrylic acid copolymer LD, methacrylic acid copolymer S, aminoalkyl methacrylate copolymer E, polyvinyl acetal diethylaminoacetate, etc. Of these polymers, ethyl cellulose may be most preferable.
Preferably, the type, degree of substitution and molecular weight of the water-insoluble polymers should be chosen for their proper use, depending on solubility of the active ingredient in water or an alcohol, the desired sustained release level and the like. These water-insoluble polymers may be used either alone or in combination. There may be further incorporated a hydrogenated oil, stearic acid, cetanol, etc. as a coating auxiliary agent, and a middle-chain triglyceride, triacetin, triethyl citrate, cetanol, etc. as a plasticizer.
The ethyl cellulose used herein preferably has an ethoxyl content of 43-50% (substitution degree of 2.2-2.6). In order to carry out the invention, ethyl cellulose has a viscosity of not less than 15 cps, preferably not less than 20 cps, more preferably 20-50 cps, at 25xc2x0 C. when dissolved at 5% by weight in a mixed solution of toluene and ethanol (8:2 w/w).
A solvent for the water-insoluble polymer may vary depending on the type of the polymer. In general, a mixture of water and a lower alcohol or a lower alcohol is preferable. In case of ethyl cellulose, a 60% or more aqueous ethanol solution is preferable. It is essential that the water-insoluble polymer be dissolved in such a solvent and that an active ingredient be dissolved or uniformly dispersed in the water-insoluble polymer solution. Where the active ingredient is of a dispersed form, it is effective to maintain an average particle diameter below 20 xcexcm for improving adhesion to a core particle and securing uniformity, and to perform a sufficient stirring for establishing uniformity.
The present invention may be applied to various active ingredients including water-soluble drugs by varying the type of water-insoluble polymers or blending ratio thereof or by additional coating of the matrix granule with a release-controlling film. Accordingly, the kind of the active ingredient to be used in this invention is not particularly restricted. The active ingredients which may be used in this invention are exemplified as follows: Diprophylline, dextromethorphan hydrobromide, phenylpropanolamine hydrochloride, belladonna (total) alkaloids, acetaminophen, theophylline, sodium salicylate, aspirin, ibuprofen, noscapine, dl-methylephedrine hydrochloride, dihydrocodeine phosphate, ethenzamide, bromhexine hydrochloride, d-chloropheniramine maleate, aminophylline, proxyphylline, caffeine, etc. These active ingredients may be used in admixture with two or more thereof.
According to the invention, it is feasible to freely control dissolution rate of the active ingredient, considering its solubility in water, according to the type of the water-insoluble polymer forming the matrix granule, the blending ratio of the water-insoluble polymer to the active ingredient and others. It is also feasible to control the dissolution rate, changing the composition of the solvent for dissolving the water-insoluble polymer. Blending ratio of the water-insoluble polymer to the active ingredient, both forming the matrix granule, may be properly selected in such a range that may control dissolution of the active ingredient, and is usually 0.7:1-3:1, preferably 0.75:1-1.25:1 in terms of weight ratio. In the production according to the invention, an amount of the water-insoluble polymer to be incorporated in the matrix granule may be preferably three times or less that of the active ingredient. However, if it is difficult to ensure the desired dissolution rate of the active ingredient by using said amount, it will be more efficient to control dissolution rate of the active ingredient by coating the matrix granule with a release-controlling film. In that case, a granule strength of the matrix granule is kept preferably not less than 3,000 g/mm2, more preferably not less than 3,500 g/mm2. This will make the coated granule hardly broken during mixing with the powdery part and compressing to tablets. Thus, it becomes feasible to lessen a change in the dissolution rate of the coated granules.
Granule strength may be controlled by choosing the type, degree of substitution and molecular weight of the water-insoluble polymer for intended use and adequately selecting a blending ratio of the water-insoluble polymer to the active ingredient.
Embodiments of the present invention are illustrated below, but the invention is not limited thereto.
If dissolution of an active ingredient contained in the matrix granule is to be controlled for a short period of time, or if dissolution of an active ingredient which is slightly soluble in water or an alcohol is to be controlled, the matrix granule may be used as such because desired dissolution control is easily accomplished without coating it with a release-controlling film. On the other hand, if dissolution of the active ingredient contained in the matrix granule is to be controlled over a long period of time, it is required to coat the granule with a release-controlling film in an amount suitable for the desired dissolution rate. The release-controlling film which may be used herein may include water-insoluble polymers as exemplified above, ethyl cellulose being preferable.
A core particle, which may be optionally used for the matrix granule, may be a spherical granule of a crystalline cellulose or a spherical granule of a lactose crystalline cellulose (For example, Celphere; manufactured by Asahi Chemical Industry Co., Ltd., Nonpareil; manufactured by Freund Industrial Co., Ltd.). An average particle diameter of the core particle ranges preferably between 100-1000 xcexcm.
The method of granulating the matrix granule using the core particle includes those using a compound coater, a rolling fluidized coater, a fluidized bed coater, etc. The granulation method without using the core granule includes wet cylindrical granulation using a kneader or a granulator, and heat-molten, agitating granulation using LEADEGE Mixer, High Speed Mixer, etc. For coating the matrix granule with a release-controlling film, an ordinary fluidized bed coater or a ventilation pan coater, etc. can be used. Subsequent curing procedure, if necessary, may also be effective. The curing procedure is preferably carried out at 70xc2x0 C. or higher.
The powdery part as used herein means the part, which comprises other components than the active ingredient (drug) and, if necessary, the active ingredients that are the same as and/or different from the active ingredient contained in the matrix granule, and which may disintegrate immediately after administration to release the granular part and simultaneously to initiate dissolution of the active ingredient (drug), if contained. The other components than the active ingredient (drug) as mentioned above may be excipients, disintegrating agents, lubricants, etc. conventionally used in tablets, for example, microcrystalline cellulose, light silicic anhydride, low substututed hydroxypropyl cellulose, hydroxypropyl cellulose, lactose, corn starch, magnesium stearate and the like, which are used in admixture therewith.
The tablet according to the invention preferably has a blending ratio by weight of the granular part to the powdery part of 1:0.5 or more. If the ratio of the powdery part is less than 0.5, a rapid disintegration into sub-units may be prevented or a poor moldability to tablet may be caused owing to mutual contact of the granular parts. An amount of the powdery part to be used has no upper limit set. No particular limitation is set on mixing of the granular part with the powdery part and compressing to tablets, which may be carried out according to a conventional method using any ordinary mixer or tablet machine. The present invention can provide sustained release tablets with little change in dissolution rate, even if a higher compression pressure has been applied. Compression pressure is usually not less than 0.6 t, preferably 1.0-2.5 t.